title: Macrophage Resistance to HIV-1 Infection Is Enhanced by the Neuropeptides VIP and PACAP.
abstract: It is well established that host factors can modulate HIV-1 replication in macrophages, critical cells in the pathogenesis of HIV-1 infection due to their ability to continuously produce virus. The neuropeptides VIP and PACAP induce well-characterized effects on macrophages through binding to the G protein-coupled receptors VPAC1, VPAC2 and PAC1, but their influence on HIV-1 production by these cells has not been established. Here, we describe that VIP and PACAP reduce macrophage production of HIV-1, acting in a synergistic or additive manner to decrease viral growth. Using receptor antagonists, we detected that the HIV-1 inhibition promoted by VIP is dependent on its ligation to VPAC1/2, whereas PACAP decreases HIV-1 growth via activation of the VPAC1/2 and PAC1 receptors. Specific agonists of VPAC2 or PAC1 decrease macrophage production of HIV-1, whereas sole activation of VPAC1 enhances viral growth. However, the combination of specific agonists mimicking the receptor preference of the natural neuropeptides reproduces the ability of VIP and PACAP to increase macrophage resistance to HIV-1 replication. VIP and PACAP up-regulated macrophage secretion of the β-chemokines CCL3 and CCL5 and the cytokine IL-10, whose neutralization reversed the neuropeptide-induced inhibition of HIV-1 replication. Our results suggest that VIP and PACAP and the receptors VPAC2 and PAC1 could be used as targets for developing alternative therapeutic strategies for HIV-1 infection.
authors.affiliation: Laboratory on Thymus Research, Oswaldo Cruz Institute/Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Jairo R
authors.initials: JR
authors.lastname: Temerozo
authors.forename: Rafael
authors.initials: R
authors.lastname: Joaquim
authors.forename: Eduardo G
authors.initials: EG
authors.lastname: Regis
authors.forename: Wilson
authors.initials: W
authors.lastname: Savino
authors.forename: Dumith Chequer
authors.initials: DC
authors.lastname: Bou-Habib
mesh_terms: D000704:Analysis of Variance; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000254:growth & development* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D054405:Chemokine CCL3; D018946:Chemokine CCL5; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D016753:Interleukin-10; D014660:Vasoactive Intestinal Peptide